Since BRAF^V600 somatic mutations were identified in melanoma, clinical and scientific knowledge has evolved rapidly. Matching patients—particularly those with melanomas harbouring these mutations—to either selective BRAF inhibitors (eg, vemurafenib and dabrafenib) or selective MEK inhibitors (eg, trametinib) has induced considerable clinical benefit. Unfortunately, symptomatic and radiographic responses to these agents fade as resistance evolves. Use of a MEK inhibitor with a BRAF inhibitor could delay development of resistance while diminishing the paradoxical activation of the MAPK pathway, which happens in normal (unmutated) tissues.

Inhibition of two targets in the same signalling pathway can seem daunting, since overlapping toxic effects might restrict dose escalation before an efficacious dose and schedule is achieved. Despite being only one enzyme apart in the MAPK signalling cascade, adverse events associated with BRAF inhibition (eg, arthralgia, non-acneiform skin rash, and hyperproliferative skin lesions including squamous-cell carcinomas) contrast strikingly with those linked to MEK inhibition (eg, acneiform skin rash, diarrhoea, and central serous retinopathy). In The Lancet Oncology, Antoni Ribas and colleagues report findings of a phase 1b study of combined BRAF and MEK inhibition with vemurafenib and cobimetinib in patients with BRAF^V600-mutated melanoma who had either recently progressed on vemurafenib (n=66) or never received a BRAF inhibitor (n=63).  Doses of both drugs were escalated and administered to patients at their respective maximum tolerated doses and schedules (established as 960 mg twice a day for vemurafenib and 60 mg daily for 21 days, with a 7-day drug holiday, for cobimetinib). Of note, an intermittent schedule of both drugs in the group that had never received a BRAF inhibitor was not investigated. Such a schedule—less tractable in the case of trametinib because of its very prolonged half-life—could allow dose escalation beyond the maximum tolerated doses of each drug alone, which could lead to more profound pathway inhibition and potentially greater efficacy.

Intratumour heterogeneity and evolution of branching tumour subclones challenge initiatives for precision medicine. Genetic diversity within tumours initiates polyclonal drug-resistance mechanisms—ie, many distinct somatic events can contribute to drug resistance in a patient with melanoma, which are acquired during exposure to targeted treatment. During BRAF monotherapy, selection of drug-resistant events could take place that might be distinct between or within metastatic sites, through mechanisms that are both dependent and independent of MAPK. After addition of a MEK inhibitor at progression, even if sites of disease with reactivation of the MAPK pathway are controlled, failure might happen because of selection of subclones that have acquired MAPK-independent resistance mechanisms, resulting in early progression. Alternatively, since MAPK reactivation happens via many routes rather than by one mechanism, the efficacy of the combination might not be equally potent across every resistance mechanism. Defining how resistance is acquired with the BRAF and MEK inhibitor combination will help resolve this conundrum. Research is needed to ascertain whether early use of a combination of BRAF and MEK inhibitors—while disease burden and permutations of genomic alterations brought about by intratumour heterogeneity are limited—is the best strategy to forestall resistance, or whether a sequential approach with appropriate patient selection could result in equivalent efficacy.

Investigators at Sanford-Burnham identifies a mechanism in the tumor microenvironment that triggers an inflammatory response, promoting tumor growth and metastasis. The findings, published in Cancer Cell, indicate a new path to anticancer therapies that incorporates targets in the tumor stroma.

Scientists has found that the loss of a protein called p62 in the cells and tissue surrounding a tumor can enhance the growth and progression of tumors. It supports the conception that therapies targeting the tumor microenvironment may be as important as targeting the tumor itself.

In the current research,  Ph.D. Jorge Moscat at Sanford-Burnham found p62 in the tissue adjacent to the tumor had the anticancer effects. However, his team previously demonstrated an opposite conclusion that p62 activation in prostate and lung cancer epithelial cells had tumor-promoting effects.

“These are highly significant observations since p62 activates another protein called mTOR which is a biological target of many ongoing clinical trials in cancer right, This potentially means that therapeutic strategies aimed at depleting an organism of p62 and inhibiting mTOR in the cells that surround the tumor may actually benefit the tumor, because tumor-suppressive activities would be inactivated.” said Maria Diaz-Meco, co-author of the study.

Uncover the mechanism of p62

To understand how p62 works, the research team introduced prostate cancer cells and monitored tumor formation in normal mice, and mice genetically engineered to lack p62. The mice without p62, called p62 knockout (KO) mice, had larger prostate tumors compared to normal mice, supporting the notion that the absence of p62 in an organism promotes cancer growth.

The researchers went on to show that p62 KO mice had increased levels of IL-6, a pro-inflammatory cytokine (a signaling molecule) that enhances tumor cell proliferation and inhibits cell death. And, the genetic events that linked p62 depletion to increased levels of IL-6 in mice were mirrored in humans.